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    Clinical Trial Results:
    A Phase II, Multi-Center, Single-Arm, Global Study of MEDI4736 Monotherapy in Patients with Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN)

    Summary
    EudraCT number
    		 2014-003295-23
    Trial protocol
    		 GB   BE   DE   HU   ES   CZ  
    Global end of trial date
    06 Jul 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Sep 2020
    First version publication date
    27 Sep 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D4193C00001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02207530
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca LP
    Sponsor organisation address
    1 MedImmune Way, Gaithersburg, United States, MD 20878
    Public contact
    Jean Fan, MD, Global Clinical Lead, AstraZeneca LP, +1 13013985080, jean.fan@astrazeneca.com
    Scientific contact
    Jean Fan, MD, Global Clinical Lead, AstraZeneca LP, +1 13013985080, jean.fan@astrazeneca.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Mar 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jul 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of durvalumab monotherapy in terms of objective response rate (ORR)
    Protection of trial subjects
    The study will be performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with International Conference on Harmonisation (ICH)/GCP, applicable regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological Samples.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Oct 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 30 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 39
    Country: Number of subjects enrolled
    France: 25
    Country: Number of subjects enrolled
    Spain: 12
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Hungary: 5
    Country: Number of subjects enrolled
    Georgia: 2
    Country: Number of subjects enrolled
    Korea, Republic of: 2
    Country: Number of subjects enrolled
    Taiwan: 1
    Country: Number of subjects enrolled
    Malaysia: 1
    Worldwide total number of subjects
    112
    EEA total number of subjects
    59
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    83
    From 65 to 84 years
    29
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 110 sites in 14 countries enrolled and screened patients. The study was conducted and managed by PRA, a contract research organization.

    Pre-assignment
    Screening details
    		 Screening took place between Day -28 and Day -1. Informed consent, study procedures and laboratory assessments (including PD-L1 testing) were undertaken over the course of 1 or more visits.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 MEDI4736
    Arm description
    		 MEDI4736 monotherapy: Durvalumab was provided at a dose of 10 mg/kg using an intravenous solution every 2 weeks until 12 months, disease progression, toxicity, or patient decision to stop therapy
    Arm type
    		 Experimental

    Investigational medicinal product name
    durvalumab
    Investigational medicinal product code
    MEDI4736
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients will receive 10 mg/kg MEDI4736 via intravenous infusion every 2 weeks (q2w) beginning on Day 0 for 12 months or until confirmed progression of disease

    Number of subjects in period 1
    		MEDI4736
    Started
    112
    Completed
    21
    Not completed
    91
         Patient decision to stop study treatment
    5
         Adverse event, non-fatal
    8
         Worsening condition under investigation
    78

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MEDI4736
    Reporting group description
    		 MEDI4736 monotherapy: Durvalumab was provided at a dose of 10 mg/kg using an intravenous solution every 2 weeks until 12 months, disease progression, toxicity, or patient decision to stop therapy

    Reporting group values
    		 MEDI4736 Total
    Number of subjects
    		 112 112
    Age Categorical
    Units: Subjects
        <=18 years
    		 0 0
        Between 18 and 65 years
    		 83 83
        >=65 years
    		 29 29
    Age Continuous
    Units: Years
        median (full range (min-max))
    		 60.0 (24 to 84) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 32 32
        Male
    		 80 80
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0
        Asian
    		 4 4
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Black or African American
    		 5 5
        White
    		 100 100
        More than one race
    		 0 0
        Unknown or Not Reported
    		 3 3
    Smoking/ Nicotine status
    Units: Subjects
        >10 Pack years|
    		 49 49
        <=10 pack years|
    		 53 53
        Unknown/ Not reported|
    		 10 10
    Nicotine Use
    Units: Subjects
        Current|
    		 10 10
        Former|
    		 59 59
        Never|
    		 43 43
    HPV status
    99 subjects were analyzed for HPV status
    Units: Subjects
        Positive|
    		 34 34
        Negative|
    		 65 65
        Unknown/ Not reported|
    		 13 13
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 1 1
        Not Hispanic or Latino
    		 109 109
        Unknown/ Not Reported
    		 2 2
    WHO/ECOG performance status
    Units: Subjects
        (0) Normal activity|
    		 34 34
        (1) Restricted activity|
    		 77 77
        Missing|
    		 1 1
    Programmed Cell Death Ligand 1 Status
    Units: Subjects
        Positive
    		 112 112
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 171.7 ( 8.96 ) -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 69.7 ( 16.36 ) -
    Body Mass Index
    Units: kg/ m^2
        arithmetic mean (standard deviation)
    		 23.44 ( 4.514 ) -

    End points

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    End points reporting groups
    Reporting group title
    MEDI4736
    Reporting group description
    		 MEDI4736 monotherapy: Durvalumab was provided at a dose of 10 mg/kg using an intravenous solution every 2 weeks until 12 months, disease progression, toxicity, or patient decision to stop therapy

    Primary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR) [1]
    End point description
    Objective response rate (per RECIST 1.1 as assessed by blinded independent central review [BICR]) is defined as the number (%) of patients with a confirmed complete response or confirmed partial response and will be based on all treated patients who are PD-L1-positive with measurable disease at baseline per BICR. Response Evaluation Criteria in Solid Tumors [RECIST] 1.1. criteria are: Complete response [CR] = disappearance of all target lesions since baseline; and partial response [PR] = at least a 30% decrease in the sum of the diameters of target lesions. Confidence interval values of 0 to 99999 were used where results were not applicable.
    End point type
    Primary
    End point timeframe
    12 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: 'No additional statistical analysis was planned for this endpoint.
    End point values
    		 MEDI4736
    Number of subjects analysed
    111
    Units: % of participants
    number (confidence interval 95%)
        Overall|
    16.2 (9.9 to 24.41)
        Smoking/nicotine status >10 pack years|
    14.6 (6.07 to 27.76)
        Smoking/nicotine status <=10 pack years|
    18.9 (9.44 to 31.97)
        Smoking/nicotine status - Missing|
    10.0 (0 to 99999)
        Substance user-Current|
    11.1 (0.28 to 48.25)
        Substance user-Former|
    15.3 (7.22 to 26.99)
        Substance user-Never|
    18.6 (8.39 to 33.40)
        HPV status-Positive|
    29.4 (15.10 to 47.48)
        HPV status-Negative|
    10.9 (4.51 to 21.25)
        HPV status-Missing|
    7.7 (0 to 99999)
    No statistical analyses for this end point

    Secondary: Best objective response

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    End point title
    		 Best objective response
    End point description
    Best objective response based on BICR assessments according to RECIST v1.1. Response required confirmation after 4 weeks. Unconfirmed complete (CR) or partial response (PR) refers to CR or PR achieved but either no confirmation assessment was performed or a confirmation assessment was performed but response was not confirmed.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 MEDI4736
    Number of subjects analysed
    111
    Units: % of participants
    number (not applicable)
        Response-Total|
    16.2
        Response-Partial response (PR)|
    15.3
        Response-Complete response (CR)|
    0.9
        Non-response (NR)-Total|
    83.8
        NR-Stable disease (SD)≥8 weeks-Total|
    9.0
        NR-SD≥8 weeks-Unconfirmed CR or PR|
    2.7
        NR-Stable disease (SD) ≥8 weeks-SD|
    6.3
        NR-Progression-Total|
    52.3
        NR-Progression-RECIST 1.1 progression|
    25.2
        NR-Progression-Death|
    27.0
        NR-Not evaluable-Total|
    22.5
        NR-Not evaluable-SD<8 weeks|
    19.8
        NR-Not evaluable-Incomplete post-baseline tests|
    2.7
    No statistical analyses for this end point

    Secondary: Duration of response- Participants remaining in response

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    End point title
    		 Duration of response- Participants remaining in response
    End point description
    Participants remaining in response - based on BICR assessments according to RECIST v1.1. An ongoing response was defined as a patient who had documented objective response and was still alive and progression-free at the time of the data cut-off.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 MEDI4736
    Number of subjects analysed
    18
    Units: % of participants
    number (not applicable)
        Remaining in response-3 months|
    100
        Remaining in response-6 months|
    76.5
        Remaining in response-9 months|
    61.8
        Remaining in response-12 months|
    37.1
        Ongoing response|
    55.6
    No statistical analyses for this end point

    Secondary: Duration of response

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    End point title
    		 Duration of response
    End point description
    Duration of objective response in patients with objective response based on BICR assessments according to RECIST v1.1. Duration of response was the time from the first documentation of complete or partial response until the date of progression (which was subsequently confirmed), death, or the last evaluable RECIST assessment for patients that did not progress. An ongoing response was defined as a patient who had documented objective response and was still alive and progression-free at the time of the data cut-off.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 MEDI4736
    Number of subjects analysed
    18
    Units: Participants
        No. progressed or died within 12 months|
    6
        No. progressed or died after 12 months|
    2
    No statistical analyses for this end point

    Secondary: Time to onset of response from first dose

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    End point title
    		 Time to onset of response from first dose
    End point description
    Time to onset of response in patients with objective response based on BICR assessments according to RECIST 1.1
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 MEDI4736
    Number of subjects analysed
    18
    Units: Months
        median (full range (min-max))
    2.00 (1.64 to 9.20)
    No statistical analyses for this end point

    Secondary: Disease control at 6 months

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    End point title
    		 Disease control at 6 months
    End point description
    Disease control (DCR) at 6 months based on BICR assessments according to RECIST v1.1. DCR at 6 months was evaluated using 2 different approaches to the length of stable disease (SD): - Method 1: Patients who had a best objective response of complete response (CR) or partial response (PR) within 24 weeks or had demonstrated SD for a minimum interval of 24 weeks following the start of study treatment. - Method 2: Patients who had a best objective response of CR or PR within 24 weeks or had demonstrated SD for a minimum interval of 16 weeks following the start of study treatment.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 MEDI4736
    Number of subjects analysed
    111
    Units: % of participants
    number (not applicable)
        METHOD 1 (M1): Disease control at 6 months|
    23.4
        M1: No disease control at 6 months|
    76.6
        M1: No disease control: Not evaluable/missing|
    27.0
        METHOD 2 (M2): Disease control at 6 months|
    33.3
        M2: No disease control at 6 months|
    66.7
        M2: No disease control: Not evaluable/missing|
    27.0
    No statistical analyses for this end point

    Secondary: Progression-free survival

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    End point title
    		 Progression-free survival
    End point description
    Progression status based on BICR assessments according to RECIST v1.1 at time of PFS analysis. Progression was defined as the time from the date of first dose until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdrew from therapy or received another anti-cancer therapy prior to progression.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 MEDI4736
    Number of subjects analysed
    112
    Units: % of participants
    number (not applicable)
        No progression|
    17.0
        No progression + under follow-up|
    12.5
        Progression-Total|
    83.0
        RECIST 1.1 progression|
    50.0
        Death in absence of RECIST 1.1 progression|
    33.0
    No statistical analyses for this end point

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    Survival status at time of overall survival analysis. 'Still in survival follow-up' includes patients known to be alive at data cut-off. 'Terminated prior to death' includes patients with unknown survival status, or who were lost to follow-up.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 MEDI4736
    Number of subjects analysed
    112
    Units: % of participants
    number (not applicable)
        Still in survival follow-up|
    24.1
        Terminated prior to death|
    6.3
        Voluntary discontinuation by subject|
    6.3
        Death|
    69.6
    No statistical analyses for this end point

    Secondary: Quality of Life

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    End point title
    		 Quality of Life
    End point description
    Improvement in quality of life was assessed using European Organisation for Research and Treatment of Cancer (EORTC) questionnaires: -The impact of treatment on Health-Related Quality of Life, functioning, and symptoms was evaluated using the EORTC QLQ-C30 v3. -Head and neck cancer-specific symptoms were evaluated using the EORTC QLQ-H&N35. Function or global health status/quality of life improvement was defined as patients with 2 consecutive assessments at least 14 days apart that showed a clinically meaningful improvement (an increase from baseline score ≥10). Symptom improvement was defined as 2 consecutive assessments at least 14 days apart that showed a clinically meaningful improvement (a decrease from baseline score ≥10). Scale improvement was defined as patients with 2 consecutive assessments at least 14 days apart that showed a clinically meaningful improvement (a decrease from baseline score ≥10).
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 MEDI4736
    Number of subjects analysed
    112
    Units: % of participants
    number (confidence interval 95%)
        EORTC QLQ-C30 Function-Physical|
    17.1 (10.1 to 27.6)
        EORTC QLQ-C30 Function-Role|
    22.9 (14.6 to 34.0)
        EORTC QLQ-C30 Function-Cognitive|
    21.0 (12.7 to 32.6)
        EORTC QLQ-C30 Function-Emotional|
    15.9 (9.1 to 26.3)
        EORTC QLQ-C30 Function-Social|
    34.7 (24.9 to 45.9)
        EORTC QLQ-C30 Symptom-Fatigue|
    21.3 (14.1 to 31.0)
        EORTC QLQ-C30 Symptom-Pain|
    26.8 (18.4 to 37.3)
        EORTC QLQ-C30 Symptom-Nausea/vomiting|
    32.3 (18.6 to 49.9)
        EORTC QLQ-C30 Global health status/QoL|
    13.5 (8.1 to 21.8)
        EORTC QLQ-H&N35 Scale-Pain in the mouth|
    24.6 (16.0 to 36.0)
        EORTC QLQ-H&N35 Scale-Swallowing|
    19.4 (11.4 to 30.9)
        EORTC QLQ-H&N35 Scale-Senses|
    34.3 (24.1 to 46.3)
        EORTC QLQ-H&N35 Scale-Speech|
    28.4 (19.7 to 39.0)
        EORTC QLQ-H&N35 Scale-Social eating|
    22.4 (14.1 to 33.7)
        EORTC QLQ-H&N35 Scale-Social contact|
    17.2 (9.6 to 28.9)
        EORTC QLQ-H&N35 Scale-Sexuality|
    25.7 (17.1 to 36.7)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time the informed consent was signed through 90 days after the last dose of the last study treatment or until another therapy was initiated.
    Adverse event reporting additional description
    AEs were reported spontaneously or in response to open questions, revealed by observation, or were changes from baseline/deterioration in tests and vital signs that met SAE criteria or led to IP discontinuation. AEs/SAEs were followed up for resolution after discontinuation or study completion and for as long as medically indicated.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    MEDI4736 10 mg/kg
    Reporting group description
    		 MEDI4736 monotherapy: Durvalumab was provided at a dose of 10 mg/kg using an intravenous solution every 2 weeks until 12 months, disease progression, toxicity, or patient decision to stop therapy

    Serious adverse events
    		 MEDI4736 10 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    43 / 112 (38.39%)
         number of deaths (all causes)
    78
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Haemorrhage
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Fatigue
         subjects affected / exposed
    3 / 112 (2.68%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Localised oedema
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchopneumopathy
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Epistaxis
         subjects affected / exposed
    2 / 112 (1.79%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung cyst
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 112 (1.79%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 112 (1.79%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Respiratory distress
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Stridor
         subjects affected / exposed
    2 / 112 (1.79%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Tachypnoea
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrostomy failure
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wound haemorrhage
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 112 (1.79%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cardiac failure
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nerve compression
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Syncope
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular encephalopathy
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dysphagia
         subjects affected / exposed
    2 / 112 (1.79%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mouth haemorrhage
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oesophageal haemorrhage
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumatosis intestinalis
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Nephritis
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Hypercalcaemia of malignancy
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Abscess neck
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 112 (3.57%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    Pulmonary sepsis
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Septic shock
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Wound infection
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 112 (1.79%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    2 / 112 (1.79%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 MEDI4736 10 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    93 / 112 (83.04%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    7 / 112 (6.25%)
         occurrences all number
    7
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    17 / 112 (15.18%)
         occurrences all number
    18
    Fatigue
         subjects affected / exposed
    26 / 112 (23.21%)
         occurrences all number
    27
    Localised oedema
         subjects affected / exposed
    6 / 112 (5.36%)
         occurrences all number
    6
    Mucosal inflammation
         subjects affected / exposed
    6 / 112 (5.36%)
         occurrences all number
    6
    Pyrexia
         subjects affected / exposed
    10 / 112 (8.93%)
         occurrences all number
    15
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    12 / 112 (10.71%)
         occurrences all number
    13
    Dyspnoea
         subjects affected / exposed
    15 / 112 (13.39%)
         occurrences all number
    18
    Oropharyngeal pain
         subjects affected / exposed
    7 / 112 (6.25%)
         occurrences all number
    7
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    10 / 112 (8.93%)
         occurrences all number
    12
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    7 / 112 (6.25%)
         occurrences all number
    7
    Weight decreased
         subjects affected / exposed
    13 / 112 (11.61%)
         occurrences all number
    13
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    11 / 112 (9.82%)
         occurrences all number
    13
    Headache
         subjects affected / exposed
    10 / 112 (8.93%)
         occurrences all number
    14
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    18 / 112 (16.07%)
         occurrences all number
    19
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    22 / 112 (19.64%)
         occurrences all number
    27
    Diarrhoea
         subjects affected / exposed
    16 / 112 (14.29%)
         occurrences all number
    28
    Dysphagia
         subjects affected / exposed
    11 / 112 (9.82%)
         occurrences all number
    11
    Nausea
         subjects affected / exposed
    22 / 112 (19.64%)
         occurrences all number
    28
    Vomiting
         subjects affected / exposed
    13 / 112 (11.61%)
         occurrences all number
    19
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    8 / 112 (7.14%)
         occurrences all number
    8
    Pruritus
         subjects affected / exposed
    12 / 112 (10.71%)
         occurrences all number
    14
    Rash
         subjects affected / exposed
    7 / 112 (6.25%)
         occurrences all number
    7
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    15 / 112 (13.39%)
         occurrences all number
    15
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    10 / 112 (8.93%)
         occurrences all number
    15
    Myalgia
         subjects affected / exposed
    7 / 112 (6.25%)
         occurrences all number
    7
    Neck pain
         subjects affected / exposed
    6 / 112 (5.36%)
         occurrences all number
    6
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 112 (6.25%)
         occurrences all number
    10
    Urinary tract infection
         subjects affected / exposed
    10 / 112 (8.93%)
         occurrences all number
    10
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    18 / 112 (16.07%)
         occurrences all number
    21
    Hypercalcaemia
         subjects affected / exposed
    10 / 112 (8.93%)
         occurrences all number
    10
    Hypokalaemia
         subjects affected / exposed
    7 / 112 (6.25%)
         occurrences all number
    9
    Hypomagnesaemia
         subjects affected / exposed
    10 / 112 (8.93%)
         occurrences all number
    15
    Hyponatraemia
         subjects affected / exposed
    8 / 112 (7.14%)
         occurrences all number
    14

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Aug 2014
    Updated study drug discontinuation requirements and sample collection schedule. Clarification of disease progression definition and PRO assessment. Inclusion of guidelines surrounding management of patients with hypersensitivity. Amended assessment language to be in alignment with other durvalumab studies.
    24 Nov 2014
    Updated inclusion and exclusion criteria surrounding previous treatment and laboratory testing. Clarification of required physical examination and vital sign assessments.
    12 Feb 2015
    Updated definition of full analysis set population and details surrounding interim analysis. Clarification of triiodothyronine and thyroxine testing requirements, consent process for PD-L1 testing and vital signs collection schedule.
    27 Feb 2015
    Updated sample size calculation, statistical analysis descriptions and vital signs assessment schedule. Clarification of PK sampling follow-up, AE follow-up schedule and inclusion and exclusion criteria. Removal of secondary endpoint relating to deep sustained response as this was not required to demonstrate durability of response. Specification of assay used to determine PD-L1 status.
    06 Aug 2015
    Updated requirements for PD-L1 sampling, required number of screened patients, survival status and PRO follow-up schedules, toxicity management guidelines, prohibited medication list and information surrounding durvalumab identity and preparation. Clarification of inclusion and exclusion criteria.
    12 Feb 2016
    Updated patient population and target population text. Estimated date of last patient last visit, scan submission and study drug discontinuation details were updated. Clarification of PD confirmation schedule, data cut-off and statistical methods for primary efficacy analysis text. The method of analysis for study endpoints was changed from immune-related response criteria to immune-related Response Evaluation Criteria in Solid Tumors version 1.1. Quality-of-life assessments were moved from secondary to exploratory objectives.
    20 Sep 2017
    Updated estimated date of last patient last visit. Addition of overall survival extension period and end of analysis sub-sections to detail the objectives of the OS extension period and the final analysis.
    18 Dec 2017
    Updated text was added to align with the updated investigator brochure. The dosing modification and toxicity management guidelines were updated to the most recent version. Text was updated to allow sites greater flexibility in the timing of survival calls post-data cut-off. Clarification of SAE variable collection and updated text to reflect the most recent immune-related AE terminology. Addition of section relating to follow-up status for withdrawn consent and lost to follow-up patients.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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